P-3: Radiation Inducible TNF-a Therapy for Prostate Cancer
P-3: Radiation Inducible TNF-a Therapy for Prostate Cancer
批准号:
8055506
负责人:
RALPH R WEICHSELBAUM
金额:
$30.02万
依托单位国家:
美国
项目类别:
财政年份:
2010
资助国家:
美国
项目状态:
已结题
起止时间:
2010-03-31 至 2014-01-31
关键词:
AblationAdenovirus VectorAndrogensBiological MarkersBlood VesselsCancer ModelCancer PatientCell DeathClinicalClinical TrialsComplementary DNADNA SequenceDataDevelopmentDoseEndothelial CellsExternal Beam Radiation TherapyFutureGene ExpressionGene Expression ProfileGenesGeneticGleason Grade for Prostate CancerGoalsHead and neck structureHumanIntensity-Modulated RadiotherapyLocal TherapyLocally Advanced Malignant NeoplasmLungMalignant NeoplasmsMalignant neoplasm of prostateMeasuresMediatingMethodsMolecular ProfilingNF-kappa BOperative Surgical ProceduresOutcomePatient SelectionPatientsPelvisPharmaceutical PreparationsPhasePhase I/II TrialPhase II/III TrialPopulationProductionPrognostic FactorProstateProstate Cancer therapyProstatectomyRadiationRadiation therapyRadiation-Sensitizing AgentsRadioRectal CancerRecurrenceResearch PersonnelResistanceSTAT1 geneSafetyStagingStaining methodStainsTNF geneTestingTherapeuticThrombosisToxic effectTumor Necrosis Factor-alphaUp-RegulationXenograft Modelantitumor agentcohortdesigndisorder controlhigh riskhuman TNF proteinimprovedinhibitor/antagonistirradiationoutcome forecastoverexpressionp65pre-clinicalprogramsradiation resistancerectalstandard caresuccesstumorvector
中文摘要
高危局限性前列腺癌患者接受标准放疗和
雄激素消融是不可接受的。在放射治疗中加入放射增敏剂是有用的,
其他局部晚期癌症,如肺癌和直肠癌。TNF-α是一种有效的放射增敏剂,
抗肿瘤剂,但毒性限制了其作为全身药物的用途。Ad.Egr-TNF.11D(TNFeradeTM,GenVec,
盖瑟斯堡,MD)是复制缺陷型E1、E3、E4缺失腺病毒载体,其编码放射性-
人TNF-α cDNA上游的可诱导DNA序列。Ad.Egr-TNF. 11 D被激活
在放射后产生肿瘤内治疗水平的TNF-α和增强的肿瘤消退
通过血管破坏和血栓形成。为了在临床上发展这一概念,
Ad.Egr-TNF. 11 D、放疗和雄激素消融,以确定联合治疗在这些患者中是否安全。
患者将进行。
人们认识到,添加诱导性局部TNF不太可能足以用于该人群,
需要探讨其他措施。此外,预测哪些患者最有可能
需要发展的利益。对于前者,TNF和辐射都能激活NF κ B,
可能对促进生存和抑制癌症和内皮细胞死亡至关重要,
成功的治疗。因此,将确定是否通过使用本发明的组合物抑制NFkB活化。
三萜类CDDO或腺病毒载体,其通过编码不可降解的(“超-
IKBa(Ad.CMV.IkBa)的“阻遏物”形式进一步增强Ad.Egr-TNF. 11 D和放射治疗的活性
在临床前前列腺癌模型中。
最后,已经证明STAT 1是由辐射诱导的,并且初步证据表明,
STAT 1的上调预示着对辐射的抵抗,提出了这样的假设,即基线水平的患者
升高的肿瘤STAT 1水平对标准放射的反应较差。因此,将确定STAT 1是否
和NFkB过表达与局部晚期前列腺增生的复发相关
癌症患者与预测的相关性将更强的患者接受放疗
比手术治疗的病人要多。
英文摘要
Outcomes for patients with high risk localized prostate cancer treated with standard radiotherapy and
androgen ablation are unacceptable. The addition of radiation sensitizing agents to radiotherapy is useful in
other locally advanced cancers such lung and rectal cancer. TNF-alpha is a potent radiosensitizing
antitumor agent, but toxicity limits its use as a systemic drug. Ad.Egr-TNF.11D (TNFeradeTM, GenVec,
Gaithersburg, MD) is a replication deficient E1, E3, E4 deleted adenoviral vector that encodes radio-
inducible DNA sequences upstream from a cDNA for human TNF-alpha. Ad.Egr-TNF.11D is activated
following radiation to produce intratumoral therapeutic levels of TNF-alpha and enhanced tumor regression
via vascular destruction and thrombosis. To develop this concept clinically an early phase clinical trial of
Ad.Egr-TNF.11D, radiotherapy, and androgen ablation to determine if the combination is safe in these
patients will be conducted.
It is recognized that addition of inducible local TNF is unlikely to be sufficient for this population and that
additional measures need to be explored. Furthermore, markers for predicting whih patients are most likely
to benefit need to be developed. In regards to the former, activation of NFkB by both TNF and radiation
may be critical to promoting survival and inhibiting both the cancer and endothelial cell death required for
successful treatment. Therefore, it will be determined if inhibition of NFkB activation through use of the
triterpenoid CDDO or an adenoviral vector that inhibits NFkB by encoding a non-degradable ("super-
repressor") form of IKBa (Ad.CMV.IkBa) further enhances the activity of Ad.Egr-TNF.11D and radiotherapy
in preclinical prostate cancer models.
Finally, it has been demonstrated that STAT1 is induced by radiation and preliminary evidence suggests that
upregulation of STAT1 predicts for resistance to irradiation, raising the hypothesis that patients with baseline
elevated tumor STAT1 levels will respond less well to standard radiation. It will thus be determined if STAT1
and NFkB overexpression are associated with recurrence in a historical group of locally advanced prostate
cancer patients with the prediction that the association will be stronger in patients treated with radiotherapy
than in patients treated with surgery.
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海外基金